Corticotrophin releasing factor CRF is the hypothalamic peptide which stimulates the secretion of ACTH, B-LPH and beta-endorphin. Arginine vasopressin (AVP) acts synergistically with CRF both in vitro and in vivo to greatly augment the release of ACTH by the pituitary. The role of CRF in clinical disturbances of the hypothalamic pituitary adrenal axis is only beginning to be unravelled. We hypothesize that abnormal CRF function is a cause of abnormal ACTH secretion in some human diseases. To document this we have chosen for investigation three discrete syndromes associated with disturbances in the regulation of ACTH: a disease with decreased secretion of ACTH, isolated ACTH deficiency; a disease of increased secretion of ACTH, Cushing's disease; and a disease of inappropriate secretion of ACTH, major depressive illness. After appropriate studies in control subjects we will investigate the role of CRF in patient by measuring changes in ACTH and cortisol in response to novel clinical tests. We recently defined a test in which graded infusion of AVP acts synergistically with ambient CRF to provide an index of endogenous CRF secretion. The response to this test and to a similar graded dose CRF stimulation test will be used to define the pathophysiology of these diseases. An autoimmune pathology involving CRF receptor is likely in some cases of isolated ACTH deficiency (but not excluded in the other diseases) because some of these patient with inadequate levels of ACTH and cortisol respond to administered AVP with release of ACTH. We have recently described a specific CRF binding protein in cultured mouse pituitary tumor cells, AtT-20 cells and will use these cells in an in vitro assay in which displacement of labeled of CRF binding to the CRF receptor is measured to identify factor(s) in patients plasma which interact with CRF or the CRF receptor. In a collaborative study we will identify by immunohistology circulating antibodies in the plasma of patients which blind to primate hypothalamic CRF cells or pituitary ACTH cells. We will also define the CRF/AVP receptor concentration on human pituitary corticotrophs in different areas of the pituitary. We will test positive plasma factor in this system also. The studies provide a broad characterization of clinical disorders of CRF function which will lead to a better understanding of the disease, better methods of treatment and better tests to study the course and recovery from these disorders.